The present invention relates to therapeutic compositions and methods of treatment for conditions having an inflammatory component, and more specifically bone, joint or connective tissue inflammation. Examples of such conditions include arthritis, including osteoarthritis and rheumatoid arthritis, rheumatism, tendonitis, bursitis, degenerative spinal disc disease, and trauma to joints, tendons, and ligaments, including sports trauma.
Inflammation, as defined in Dorland's Medical Dictionary, is “a localized protective response elicited by injury or destruction of tissues which serves to destroy, dilute or wall off both the injurious agent and the injured tissue.” It is characterized by dilation of the microvasculature, leakages of the elements of blood into the interstitial spaces, and migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema (redness), edema (fluid buildup), hyperalgesia (tenderness), heat, and pain. During this complex response, chemical mediators such as histamine, 5-hydroxytryptamine, various chemotactic factors, bradykinin, leukotrienes, and prostaglandins are liberated locally. Phagocytic cells migrate into the area, and cellular lysosomal membranes may be ruptured, releasing lytic enzymes. All of these events may contribute to the inflammatory response.
Inflammation in patients with rheumatoid arthritis probably involves the combination of an antigen (gamma globulin) with an antibody (rheumatoid factor) and complement causing the local release of chemotactic factors that attract leukocytes. The leukocytes phagocytose the complexes of antigen-antibody and complement and also release the many enzymes contained in their lysosomes. These lysosomal enzymes then cause injury to cartilage and other tissues, and this furthers the degree of inflammation. Cell mediated immune reactions may also be involved. Prostaglandins are also released during this process.
Prostaglandins, which are likely to be generated in inflammation, cause erythema and increase local blood flow. Two important vascular effects of prostaglandins that are not generally shared by other mediators of inflammation are a long-lasting vasodilator action and a capacity to counteract the vasoconstrictor effects of substances such as norepinephrine and angiotensin.
A number of mediators of inflammation increase vascular permeability (leakage) in the post-capillary and collecting venules. In addition, migration of leukocytes into an inflamed area is an important aspect of the inflammatory process.
Although osteoarthritis does not always include the same intense inflammatory component as rheumatoid arthritis, it does involve damage to cartilage and other tissues, resulting in pain, deformity, and limitation of motion of joints, in a similar fashion to rheumatoid arthritis.
Osteoarthritis is divided into two categories, primary and secondary osteoarthritis. In primary osteoarthritis, the degenerative wear-and-tear process generally occurs after the fifth and sixth decades, with no predisposing abnormality apparent. The cumulative effects of decades of use leads to the degenerative changes by stressing the integrity of the collagen matrix of the cartilage. Damage to the cartilage results in the release of enzymes that destroy collagen components. With aging, there is a decreased ability to restore and synthesize normal collagen structures.
Secondary osteoarthritis is associated with some predisposing factor responsible for the degenerative changes. Various predisposing factors in secondary osteoarthritis include congenital abnormalities in joint structure or function (e.g. excessive joint mobility and abnormally shaped joint surfaces), trauma (obesity, fractures along joint surfaces, surgery, etc.), crystal deposition, presence of abnormal cartilage, and previous inflammatory disease of joint (rheumatoid arthritis, gout, septic arthritis, etc.)
The causes of osteoarthritis are, thus, believed to include one or more of the following conditions or imbalances in the body's chemistry: excessive mobility/joint instability, age-related changes in collagen matrix repair mechanisms, hormonal and sex factors, altered biochemistry, genetic predisposition, inflammation, fractures and mechanical damage, inflammatory joint disease, joint immobilization, poor nutritional history, and others.
As anyone who has been afflicted by this disease can attest, the onset of osteoarthritis can be very subtle, morning joint stiffness often being the first symptom. As the disease progresses, there is pain on motion of the involved joint, that is made worse by prolonged activity and relieved by rest. There is usually only minor inflammation.
The specific clinical picture varies with the joint involved. Disease of the hands leads to pain and limitation of use. Knee involvement produces pain, swelling, and instability. Osteoarthritis of the hip causes local pain and a limp. Spinal osteoarthritis is very common and may result in compression of nerves and blood vessels, causing pain and vascular insufficiency.
The inflammatory response is any response characterized by inflammation as defined above. It is well known to those skilled in the medical arts that the inflammatory response causes much of the physical discomfort, i.e., pain and loss of function, that has come to be associated with different diseases and injuries. Accordingly, it is a common medical practice to administer pharmacological agents which have the effect of neutralizing the inflammatory response. Agents having these properties are classified as anti-inflammatory drugs. Anti-inflammatory drugs are used for the treatment of a wide spectrum of disorders, and the same drugs are often used to treat different diseases. Treatment with anti-inflammatory drugs is not for the disease, but most often for the symptom, i.e., inflammation.
The anti-inflammatory, analgesic, and anti-pyretic drugs are a heterogeneous group of compounds, often chemically unrelated, which nevertheless share certain therapeutic actions and side-effects. Corticosteroids represent the most widely used class of compounds for the treatment of the inflammatory response. Proteolytic enzymes represent another class of compounds which are thought to have anti-inflammatory effects. Hormones which directly or indirectly cause the adrenal cortex to produce and secrete steroids represent another class of anti-inflammatory compounds. A number of nonhormonal anti-inflammatory agents have been described. These agents are generally referred to as non-steroidal anti-inflammatory drugs (NSAIDS). Among these, the most widely used are the salicylates. Acetylsalicylic acid, or aspirin, is the most widely prescribed analgesic-antipyretic and anti-inflammatory agent. Examples of steroidal and non-steroidal anti-inflammatory agents are listed in the Physicians Desk Reference, 54th Edition, 2000 (see pp. 202 and 217 for an index of such preparations).
The natural and synthetic corticosteroid preparations cause a number of severe side effects, including elevation of blood pressure, salt and water retention, and increased potassium and calcium excretion. Moreover, corticosteroids may mask the signs of infection and enhance dissemination of infectious microorganisms. These hormones are not considered safe for use in pregnant females, and long-term corticosteroid treatment has been associated with gastric hyperactivity and/or peptic ulcers. Treatment with these compounds may also aggravate diabetes mellitus, requiring higher doses of insulin, and may produce psychotic disorders. Hormonal anti-inflammatory agents which indirectly increase the production of endogenous corticosteroids have the same potential for adverse side-effects.
NSAIDS are synthetic biochemical compounds which can be toxic at high doses with a wide spectrum of undesirable side-effects. For example, salicylates contribute to the serious acid-base balance disturbances that characterize poisoning by this class of compounds. Salicylates stimulate respiration directly and indirectly. Toxic doses of salicylates cause central respiratory paralysis as well as circulatory collapse secondary to vasomotor depression. The ingestion of salicylate may result in epigastric distress, nausea, and vomiting. Salicylate-induced gastric bleeding is well known. Salicylates can produce hepatic injury, and lead to a prolongation of clotting time. Therefore, aspirin should be avoided with patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency, or hemophilia, because the inhibition of platelet homeostasis by salicylates can result in hemorrhage. Salicylate intoxication is common, and over 10,000 cases of serious salicylate intoxication are seen in the United States every year, some of them being fatal, and many occurring in children. See Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., 1992.
Another side effect of aspirin and other NSAIDs that is often not mentioned is their inhibition of cartilage repair (i.e. inhibition of collagen matrix synthesis) and acceleration of cartilage destruction in experimental studies. Since osteoarthritis is caused by a degeneration of cartilage, it appears that, while NSAIDs are fairly effective in suppressing the symptoms, they possibly worsen the condition by inhibiting cartilage formation and accelerating cartilage destruction. This adverse effect of NSAID therapy has been upheld in studies which have shown that NSAIDs use is associated with acceleration of osteoarthritis and increased joint destruction. Simply stated, NSAIDs appear to suppress the symptoms but accelerate the progression of osteoarthritis. Accordingly, in spite of the large number of anti-inflammatory agents that are currently available, there still exists a need for a safe, effective anti-inflammatory product which is free of side-effects and adverse reactions.
Natural ingredients, including Ayurvedic formulations, have been used to treat bone and joint inflammation, especially in eastern countries, and, increasingly, in western countries. Such natural ingredients include, for example, cartilage, chondroitin, glucosamine, proteolytic and other enzymes, and herbs, such as the gummy extract of B. serrata, Ashwagandha root and ginseng root. Although such natural ingredients generally do not lead to the kind of side effects observed with the steroidal and non-steroidal anti-inflammatory drugs (NSAIDS) discussed above, many of these natural ingredients do not always provide sufficient relief of pain or restoration of significant function and use of inflamed tissue, e.g., joints. However, glucosamine and chondroitin have been found to contribute to restoring such function and use.
Although glucosamine generally does not provide the same rapid temporary relief of inflammation and pain as aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS), it plays several key roles in the preservation and rebuilding of joint tissues. Namely, it stimulates the cartilage cells to produce glycosaminoglycans and proteoglycans, which maintain healthy joints and contribute to rebuilding connective tissue, and it is one of the main ingredients of the synovial fluid that lubricates and provides nutrients for the joint structures. By participating in the preservation and rebuilding of joint tissues, it is believed that glucosamine can contribute to long term relief of a wide range of degenerative and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, degenerative spinal disc disease, tendinitis, bursitis, and trauma to joints, tendons and ligaments, and may actually reverse the underlying disease process, in many cases.
Chondroitins, e.g. chondroitin sulfate, have also been found to play a role in the preservation and rebuilding of joint tissues. In a similar fashion to glucosamine, chondroitins have been found to stimulate cartilage cells to produce the needed proteoglycans and to inhibit the enzymes that break down proteoglycans. Chondroitin sulfate in particular also functions to draw fluid into the proteoglycan molecules. This fluid acts as a shock absorber for the joint tissue and also carries nutrients into the cartilage.
Although the administration of glucosamine appears to be an effective treatment for many conditions having an inflammatory component, it is not free of side effects. In that regard, it has been found that high blood serum levels of glucosamine can interfere with glucose regulation in both normal individuals and individuals with diabetes mellitus. The high levels of glucosamine can induce an insulin resistance response, resulting in reduced rates of insulin—mediated glucose uptake by the liver, skeletal muscle, and adipose tissue (fat cells). If uncontrolled, insulin resistance can lead to hyperglycemia and possibly glucose toxicity. In normal (i.e., non-diabetic) individuals, hyperglycemia can interfere with cellular metabolism and the mechanics for insulin-induced glucose disposal. The hyperglycemia itself can worsen insulin resistance, thus contributing to a vicious cycle that makes glycemic regulation more difficult. Moreover, hyperglycemia and insulin resistance are major contributing factor in the pathogenesis of non-insulin-dependant diabetes mellitus (NIDDM).
The effects of high glucosamine levels on patients with NIDDM are typically more pronounced, since such patients generally affect glycemic regulation with dietary control. Thus, in such patients the cause and effect of insulin resistance and hyperglycemia on each other result in worsening the diabetic state and making glycemic regulation more difficult. Moreover, clinical studies have shown that hyperglycemia is the cause of most if not all of the chronic complications of diabetes. Insulin resistance induced by high levels of glucosamine can also have dramatic effects on patients with insulin dependent diabetes mellitus (IDDM) by again initiating a vicious cycle that worsens the diabetic state and makes glycemic regulation more difficult, possibly leading to glucose toxicity.
Thus, there is a need for new treatments of conditions having an inflammatory component, such as inflamed bones and/or joints, that avoid the disadvantages of known treatments, including the disadvantages described above.